Project Summary: The Integrated Pathology and Genomics Core provides state-of-the-art analytic services for lung cancer samples spanning the full spectrum from initial sample handling and processing, to microscopic analysis by certified anatomic pathologists, to immunophenotypic analysis, to molecular genetic and genomic analysis. This work constitutes the backbone of lung cancer management, and enables the diagnosis and proper treatment selection for patients with lung cancers of all types, and also enables research into cancer biology, etiology, and management. Our pathology core has supported work that has led to major advances in the understanding of lung cancer biology, and associated management thereof, including seminal discoveries of the importance of mutations in EGFR, ALK, ROS1, and MET in lung cancer, the diagnosis and management of which have become the international standard-of-care in this area of medicine. In the same manner, we intend to continue our work to advance the understanding and care of lung cancer, by supporting the new projects proposed herein, with a combination of standard-of-care and innovative new cutting-edge technologies. In this SPORE proposal, we will support each of the proposed projects with a combination of standard-of-care clinical pathology services - such as histologic characterization of tumors, immunohistochemical assessment of protein expression, and massively parallel sequencing of tumor DNA - and innovative new techniques. Among the innovative new techniques to be deployed for this project are customized allele-specific PCR assays for individual fusion transcripts to enable ultrasensitive monitoring of cell-free circulating ALK rearrangements in plasma samples, cyclic immunofluorescence and transcriptomics for simultaneous in situ spatial expression of multiple proteins and transcripts involved in various biochemical pathways, and multiplexed ion beam imaging to provide high-order assessment of immune cell infiltrates within and adjacent to cancers.